Pharmaceutical composition containing bupropion hydrochloride and a stabilizer

ABSTRACT

Novel, stable formulations of bupropion hydrochloride are provided which will maintain at least 80% of initial bupropion hydrochloride potency after one year. Methods of inhibiting degradation of bupropion hydrochloride and methods of preparing stable formulations of bupropion hydrochloride are also provided.

This application is a divisional application of Ser. No. 09/000,999,filed Dec. 30, 1997, U.S. Pat. No. 6,221,917.

BACKGROUND OF THE INVENTION

Bupropion hydrochloride is a common antidepressant sold in immediaterelease, modified release, and extended release tablet forms. See U.S.Pat. Nos. 3,819,706 and 3,885,046. As with many pharmaceuticals, thestability of bupropion hydrochloride is affected by a number of factorsincluding formulation microenvironments and storage conditions.

One formulation of bupropion hydrochloride is taught by Ruff et al.,U.S. Pat. No. 5,358,970 to prevent or inhibit degradation of bupropionhydrochloride using one of the stabilizers L-cysteine hydrochloride,glycine hydrochloride, malic acid, sodium metabisulfite, citric acid,tartaric acid and L-cystine dihydrochloride. These solid dosage formswere prepared using alcohol granulation technology. However, granulationtechnology is labor intensive and costly. In addition special proceduresare necessary to address safety and environment issues involving the useof alcohol.

Accordingly, stable bupropion hydrochloride formulations prepared bysafe, cost effective methods are greatly desired. The present inventionprovides such stable bupropion hydrochloride formulations.

DESCRIPTION OF THE INVENTION

In accordance with the present invention is provided a pharmaceuticalcomposition comprising bupropion hydrochloride and a pharmaceuticallyacceptable stabilizer.

Bupropion Hydrochloride is described in U.S. Pat. Nos. 3,819,706 and3,885,046 and the Merck Index, Twelfth Edition, entry no. 1523.

Stabilizer, as the term is used herein, means a compound which inhibitsor prevents the degradation of bupropion hydrochloride so that it can beused in a pharmaceutical formulation while retaining much of itspotency. Stabilizers useful in accordance with the present inventionretain at least about 80% of the potency of bupropion hydrochloride andpreferably over 90% of potency after one year of storage at roomtemperature (59-77° C.) at 35-60% humidity. Thus, a tablet containing100 mg of bupropion hydrochloride should retain at least 80 mg andpreferably more than 90 mg of bupropion hydrochloride at the end of 1year in the presence of stabilizers of the present invention.

Suitable stabilizers have an aqueous suspension pH of from about 0.9 toabout 4.0 at a concentration of about 6% w/w. Further, said stabilizershave solubility in water at 20° C. of less than about 10 gstabilizer/100 g water.

The stability of the formulation was tested in accordance with industrystandards by storage for four to twelve weeks at about 40° C. and about75% relative humidity. Formulations containing stabilizers of thepresent invention stored under these conditions retain at least 80% ofthe bupropion hydrochloride in the composition at the time of storage.In many instance formulations of the present invention retain more than85% and ideally retain at least 90% of bupropion hydrochloride in thecomposition at the time of storage. Standard procedures such as HPLC maybe used to determine the amount of active ingredient remaining afterstorage.

The aqueous suspension pH of the stabilizers of this invention isdetermined by adding 3.75 grams of stabilizer to 60 grams of deionizedwater in a Pyrex® beaker. The resulting mixture is stirred forapproximately 5 minutes, using a stir plate and a magnetic stir bar. Theresulting suspension or dispersion is examined using a Corning® pH MeterModel 355. Suspensions are stirred with a magnetic stir bar duringanalysis. Measurements are performed in duplicate and the averagethereof is used.

Stabilizers of the present invention include dicarboxylic acids meetingthe aforementioned criteria and more specifically include, but are notlimited to, oxalic, succinic, adipic, fumaric and phthalic acids, orcombinations thereof. Fumaric acid is a preferred stabilizer.

Pharmaceutical compositions of the present invention may optionallyinclude any conventional ingredients for improving the physicalproperties, visual appearance or odor of the pharmaceutical. Examplesinclude, but are not limited to, lubricants such as talc; binders suchas starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose andpolyvinylpyrrolidone; diluents such as microcrystalline cellulose andlactose; disintegrants such as sodium starch glycolate, crospovidone andcroscarmellose sodium; and colorants.

The total amount of inactive ingredient in the formulation, includingthe amount of stabilizer, is preferably more than 50% of the weight ofbupropion hydrochloride in the composition and less than 650% of theweight of bupropion hydrochloride. The amount of stabilizer may be fromabout 10% to 100% of the weight of bupropion hydrochloride and isideally about 10% to about 40% of the weight of bupropion hydrochloridein the composition. Most preferably, the amount of stabilizer is fromabout 15% to about 30% of the weight of bupropion hydrochloride.Furthermore about 1% to about 40% of the total weight of the tablet orcapsule may be stabilizer. More preferably, stabilizer accounts forabout 3% to about 6% of the total weight of the composition. Thesuitable amount of stabilizer is based on the label strength ofbupropion hydrochloride in the pharmaceutical formulation in soliddosage form and can be determined by one skilled in the art.

Pharmaceutical compositions of the present invention generally contain25 mg to 500 mg of bupropion hydrochloride. More preferred compositionsof the invention contain 50 mg, 75 mg, 100 mg or 150 mg of activeingredient and may be in the form of tablets, caplets or capsules.Immediate release, modified release, and extended release profiles, orcombinations thereof, are encompassed by the present invention.

Pharmaceutical compositions of the present invention are prepared by dryblending followed by direct compression. For instance, the ingredientsare screened and blended in an industrial blender such as a Gemco®Double Cone Blender. The blended materials are milled such as with aModel D-6 Fitzmill®. Blending may be performed to achieve semi-geometricdilution. Thereafter, the ingredients are directly compressed intotablets using, for instance, a Kikusui Libra® tablet compressionmachine.

The following examples are illustrative, but are not limiting of thepresent invention. Throughout the examples, NF and USP are designationsfor standards published in the National Formulary and U.S.Pharmacopoeia, respectively.

EXAMPLES Example 1

The formulation contained the following ingredients in the followingamounts:

Weight per Tablet (mg) Ingredient 75 mg potency Bupropion Hydrochloride75.0 Cellulose, Microcrystalline, NF 332.0 Talc, USP 23.0 Fumaric Acid,NF 18.0 Hydroxypropyl Cellulose, EXF, NF 10.0 Coating Core Weight 458.0Chromatone ® P DDB8361-W 12.56 Polyethylene Glycol 400, NF 1.10Polysorbate 80, NF 0.14 Purified water USP 0.1 mL TOTAL 471.8

The powder ingredients were weighed out for a 56,000 tablet batch size.

The following ingredients were sifted through a clean #20 mesh screen:

Cellulose, Microcrystalline, NF

Bupropion Hydrochloride

Hydroxypropyl Cellulose, EXF, NF

Fumaric Acid, NF

The screened material was transferred into a Gemco Double Cone Blenderand blended for ten (10) minutes. Thereafter, the remaining CelluloseMicrocrystalline NF was transferred into the Gemco Double Cone Blenderand blended for ten (10) minutes. The blended material was milledthrough a Model D-6 Fitzmill equipped with a #1 plate, knives forward atmedium speed. Talc, USP was passed through a #30 mesh screen into themilled material. The material was transferred into the Gemco Double ConeBlender and blended for ten (10) minutes. The blended material wascompressed on a Kikusui Libra tablet compression machine at a weight ofabout 0.458 grams per tablet.

The coating solution was prepared as follows:

Purified water USP was added to a clean manufacturing tank equipped witha clean Mixer.

The following ingredients were added to the manufacturing tank:

Polyethylene Glycol 400, NF

Polysorbate 80, NF

The mixer was turned on.

Chromatone® P DDB8361-W was slowly added to the manufacturing tank.After the ingredients were added, the mixing was continued until auniform suspension was achieved. The pan load amounts and solutionamounts were calculated for solution application using the Hi Coater 60.

The tablet cores were loaded into the pan coater. The tablet bed waspreheated until the exhaust air temperature was between 37° and 48° C.(approximately 43° C.). The pan speed was adjusted to approximately 8RPM before starting the spray cycle. The spray cycle was activated. Theexhaust temperature was maintained between 37° C. and 48° C. throughoutthe cycle. After the proper amount of solution was applied, the coatedtablets were dried. Tablets were coated to an approximate weight gain of24 mg per tablet.

Product stability data were obtained for this formulation stored for 12weeks at 40° C., 75% relative humidity. Potency was determined usingHPLC. Product stability data are presented in Table 1.

TABLE 1 Weeks Potency (%) 0 99.9 4 97.1 12 95.8

Example 2

The formulation contained the following ingredients in the followingamounts:

Weight per Tablet (mg) Ingredient 75 mg potency Core BupropionHydrochloride 75.0 Cellulose, Microcrystalline, NF 334.0 Talc, USP 23.0Fumaric Acid, NF 18.0 Hydroxypropyl Cellulose, EXF, NF 10.0 Core Weight460.0 Coating Chromatone ® P DDB8440-OR 12.56 Polyethylene Glycol 400,NF 1.10 Polysorbate 80, NF 0.14 Purified water USP 0.1 mL TOTAL 473.8

The powder ingredients were weighed out for a 500,000 tablet batch size.

The blended material was prepared as described in Example 1.

The blended material was then compressed on a Kikusui Libra tabletcompression machine. Tablets were compressed at a weight of about 0.460grams per tablet. Compression was performed in a room with temperaturebetween 55°14 85° F. and low humidity (approximately 30% RelativeHumidity).

The coating solution was prepared as follows:

Ninety-eight percent (98%) of purified water USP was added to a cleanmanufacturing tank equipped with a clean Chemineer Mixer with afour-inch blade. The Chemineer mixer was turned on and the setting wasadjusted to 2-10 psi.

The following ingredients were added to the manufacturing tank:

Polyethylene Glycol 400, NF

Polysorbate 80, NF

After the ingredients were added, the mixer setting was adjusted to 1-4psi to minimize foaming. The Polyethylene Glycol and Polysorbate 80, NFcontainers were rinsed using remaining 2% of Purified Water USP and therinse water was added to the tank. Mixing was continued forapproximately ten (10) minutes. The mixer setting was adjusted to 30-60psi. Mixing was continued for approximately twenty (20) minutes.

Chromatone® P DDB8440-OR was added to the manufacturing tank. The mixersetting was reduced to 1-4 psi to reduce foaming and mixing continuedfor thirty (30) minutes. The pan load amounts and solution amounts werecalculated for solution application using the Hi Coater 130.

The spray guns were installed in the pan coater unit as follows:

Spray Gun Nozzle Size: Air Cap 025-R, Liquid Nozzle 012.

Hi Coater 130:

Atomizing Air: 140 to 150 SLPM

Pattern Air: 190 to 200 SLPM

Four guns to equal 250-500 ml/min.

Solution was stirred with the mixer setting of 1-2 psi at all times.

The tablet cores were loaded into the pan coater. The tablet bed waspreheated until the exhaust air temperature was between 37° C. and 48°C. (approximately 43° C.). The pan speed was adjusted to 5-9 RPM beforestarting the spray cycle. The spray cycle was activated. The exhausttemperature was maintained between 37° C. and 48° C. throughout thecycle. After the proper amount of solution was applied, the coatedtablets were dried for approximately two (2) minutes. Steps wererepeated for all pans to coat all tablets in the batch. All tablets werecoated to an approximate weight gain of 13.8 mg per tablet.

Product stability data were obtained for this formulation stored for 12weeks at 40° C., 75% relative humidity. Potency was determined usingHPLC. Data are presented in Table 2.

TABLE 2 Weeks Potency (%) 0 100.8 4 94.9 8 92.5 12 91.0

Example 3

The formulation contained the following ingredients in the followingamounts:

Weight per Tablet (mg) Ingredient 100 mg potency Bupropion Hydrochloride100.0 Cellulose, Microcrystalline, NF 442.0 Talc, USP 30.7 Fumaric Acid,NF 24.0 Hydroxypropyl Cellulose, EXF, NF 13.3 Core Weight 610.0 CoatingChromatone ® P DDB8440-OR 16.8 Polyethylene Glycol 400, NF 1.5Polysorbate 80, NF 0.2 Purified water USP 0.14 mL TOTAL 628.5

The powder ingredients were weighed out for a 42,001 tablet batch sizeand prepared as described in Example 1. The blended material wascompressed on a Kikusui Libra tablet compression machine at a weight ofabout 0.610 grams per tablet. Tablets were coated according to theprocedure described in Example 1. Product stability data were obtainedfor this formulation stored for 12 weeks at 40° C., 75% relativehumidity. Potency was determined using HPLC. Product stability data arepresented in Table 3.

TABLE 3 weeks Potency (%) 0 97.7 4 91.3 8 93.4 12 88.1

Example 4

The formulation contained the following ingredients in the followingamounts:

Weight per Tablet (mg) Ingredient 100 mg potency Core BupropionHydrochloride 100.0 Cellulose, Microcrystalline, NF 445.0 Talc, USP 30.7Fumaric Acid, NF 24.0 Hydroxypropyl Cellulose, EXF, NF 13.3 Core Weight613.0 Coating Chromatone ® P DDB8440-OR 16.8 Polyethylene Glycol 400, NF1.5 Polysorbate 80, NF 0.2 Purified water USP 0.14 mL TOTAL 631.5

The powder ingredients were weighed out for a 375,000 tablet batch sizeand prepared as described as in Example 2. Tablets were compressed at acompression weight of about 0.613 grams per tablet. Tablets were coatedas described in Example 2 to an approximate weight gain of 18.5 mg pertablet.

Product stability data were obtained for this formulation stored for 12weeks at 40° C., 75% relative humidity. Potency was determined usingHPLC. Product stability data are presented in Table 4.

TABLE 4 weeks Potency (%) 0 98.7 4 94.4 8 93.9 12 92.1

Example 5

The formulation contained the following ingredients in the followingamounts:

Weight per Tablet (mg) Ingredient 75 mg potency Bupropion Hydrochloride75.0 Cellulose, Microcrystalline, NF 332.0 Talc, USP 23.0 Fumaric Acid,NF 18.0 Hydroxypropyl Cellulose, EXF, NF 10.0 TOTAL 458.0

The powder ingredients were weighed out for a 45,000 tablet batch size.The composition was prepared as described in Example 1. Tablets werecompressed at a compression weight of about 0.458 grams per tablet.Tablets were film coated as described in Example 2 to an approximateweight gain of 4.25% (19.5 mg).

Product stability data were obtained for this formulation stored for 12weeks at 40° C., 75% relative humidity. Potency was determined usingHPLC. The following product stability data shown in Table 5 wereobtained for this formulation.

TABLE 5 Weeks Potency (%) 0 98.5 4 95.0 8 93.0 12 89.8

What is claimed is:
 1. A method for preparing a stable composition ofbupropion hydrochloride in solid form comprising: dry blending bupropionhydrochloride and solid stabilizer to equally distribute the components;dry milling the blended material; and preparing a solid dosage form. 2.The method of claim 1 wherein the stabilizer is fumaric acid.